C850Y
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialCysteine → Tyrosine at position 850 in wolframin's C-terminal lumenal domain. ClinVar Conflicting classifications including Wolfram syndrome 1. AlphaMissense 0.975, DynaMut2 ΔΔG -0.42 kcal/mol (destabilising). The C850 partner of C847Y in the inferred C847-C850 disulfide.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | L817 | — | Lost |
| Hydrogen bond | C847 | C847 | Preserved |
| Polar contact | — | S816 | Gained |
| Polar contact | — | R818 | Gained |
| Polar contact | C847 | C847 | Preserved |
| Polar contact | A852 | — | Lost |
| Van der Waals | — | C847 | Gained |
| Hydrophobic | — | R818 | Gained |
| Hydrophobic | C847 | — | Lost |
Lost / gained / preserved interatomic contacts at the variant residue, from the DynaMut2 (Arpeggio) interaction analysis of the wild-type and energy-minimized mutant structures.
Computational Predictions
This variant is in a water-facing region, which is the regime the stability predictor was built and benchmarked for. Ordinary predictor error still applies.
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). Classic Wolfram syndrome is recessive: a single copy does not produce it, and this classification says nothing about a carrier's own risk.
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes.
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: 1★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in European (non-Finnish): AF 0.00025% (3 of 1,179,970 alleles), in line with the global figure.
No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| South Asian · under-sampled | 0.0011% | 1 / 91,090 | 0 | — |
| European (non-Finnish) | 0.00025% | 3 / 1,179,970 | 0 | ~1 in 196660 |
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
Structural Context
Position 850 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places C850 within 5 Å of MET851 (2.5 Å), ASN849 (2.5 Å), and CYS847 (3.6 Å — partner of C847Y Atlas card, possible disulfide). The C847-C850 distance of 3.6 Å is the strongest disulfide-distance signal in this batch.
Replacing C850 with tyrosine eliminates this potential disulfide and introduces aromatic volume. Combined with C847Y (Atlas card adjacent), both ends of the inferred C847-C850 disulfide are now known to be pathogenic when mutated.
The |ΔΔG| of 0.42 reflects fold accommodation. AlphaMissense's 0.975 confirms severe functional consequence. pLDDT 74 is borderline but above the IDR threshold.
Druggability Assessment
Mechanism is loss of the inferred C847-C850 disulfide. Therapeutic strategy: same C847-C850 microregion as C847Y.
Why this matters
Feed this card to Wolfram Intelligence
Download the C850Y PDF below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals — guanidinium mimetics, sigma-1 agonist docking, NAC thiol-capping. NAC is already on the bench-testing list.